SARS-CoV-2 VOC type and biological sex affect molnupiravir efficacy in severe COVID-19 dwarf hamster model
Lieber et al.
, SARS-CoV-2 VOC type and biological sex affect molnupiravir efficacy in severe COVID-19 dwarf hamster model
, Nature Communications, doi:10.1038/s41467-022-32045-1
Roborovski dwarf hamster and in vitro
study finding molnupiravir efficacy varied significantly by SARS-CoV-2 variant in the hamster model, in contrast to no significant difference seen in cultured cells and human organoids. Efficacy for omicron in the hamster model varied significantly based on biological sex.Concerns have been raised that the mutagenic mechanism of action may create dangerous variants or cause cancer [Hadj Hassine, Swanstrom]. See [Fountain-Jones, Sanderson, ] for analysis of variants potentially created by molnupiravir.
Lieber et al., 29 Jul 2022, USA, peer-reviewed, 15 authors.
Abstract: nature communications
SARS-CoV-2 VOC type and biological sex
affect molnupiravir efﬁcacy in severe
COVID-19 dwarf hamster model
Received: 1 March 2022
Check for updates
Accepted: 14 July 2022
Carolin M. Lieber1,5, Robert M. Cox 1,5, Julien Sourimant 1, Josef D. Wolf 1,
Kate Juergens2, Quynh Phung2, Manohar T. Saindane3, Meghan K. Smith 3,
Zachary M. Sticher 3, Alexander A. Kalykhalov3, Michael G. Natchus3,
George R. Painter3, Kaori Sakamoto4, Alexander L. Greninger2 &
Richard K. Plemper 1
SARS-CoV-2 variants of concern (VOC) have triggered infection waves. Oral
antivirals such as molnupiravir promise to improve disease management, but
efﬁcacy against VOC delta was questioned and potency against omicron is
unknown. This study evaluates molnupiravir against VOC in human airway
epithelium organoids, ferrets, and a lethal Roborovski dwarf hamster model of
severe COVID-19-like lung injury. VOC were equally inhibited by molnupiravir
in cells and organoids. Treatment reduced shedding in ferrets and prevented
transmission. Pathogenicity in dwarf hamsters was VOC-dependent and
highest for delta, gamma, and omicron. All molnupiravir-treated dwarf hamsters survived, showing reduction in lung virus load from one (delta) to four
(gamma) orders of magnitude. Treatment effect size varied in individual dwarf
hamsters infected with omicron and was signiﬁcant in males, but not females.
The dwarf hamster model recapitulates mixed efﬁcacy of molnupiravir in
human trials and alerts that beneﬁt must be reassessed in vivo as VOC evolve.
By May 2022, SARS-CoV-2 has resulted in over 522 million cases and
>6.2 million deaths worldwide1. Vaccines are widely available2,3, but
recuring global infection waves have been fueled by limited longevity
of vaccine-induced immunity, the hesitancy of population subgroups
to vaccinate4,5, and increasingly contagious and/or vaccine-insensitive
variants of concern (VOC) alpha (B.1.1.7 lineage), beta (B.1.351 lineage),
gamma (P.1 lineage), delta (B.1.617.2 lineage), and omicron (B1.1.529
lineage)6,7. VOC delta was the prevalent circulating variant during
Summer and Fall 2021 due to replication to high titers, prolonged
shedding from infected individuals, and propensity to induce breakthrough infections in vaccinees8–10. Since its ﬁrst appearance in
November 2021, VOC omicron has rapidly replaced delta as the
dominant circulating strain in most geographical regions11, propelled
by sharply reduced sensitivity to neutralizing antibodies directed
against earlier lineages and greatly increased infectivity12. Although
clinical signs associated with VOC omicron are typically milder than
those of its predecessors, record-high daily infection rates have driven
high absolute hospitalization numbers, creating an urgent need for
therapeutics to improve disease management.
Molnupiravir was the ﬁrst orally available SARS-CoV-2 inhibitor
approved for outpatient use against COVID-1913. Intermediate results
of the early months of a large efﬁcacy trial revealed an encouraging
50% reduction in hospitalizations in the treatment group, but later
analysis of the full dataset showed only a 30% lower hospitalization
rate overall14. Based on the geographical location of trial participants
and VOC prevalence in the earlier versus later phase of the trial, an
Center for Translational Antiviral Research, Institute for Biomedical Sciences, Georgia State..
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